title: TNF-α downregulates inhibitory neurotransmission through protein phosphatase 1-dependent trafficking of GABA(A) receptors.
abstract: Inflammation has been implicated in the progression of neurological disease, yet precisely how inflammation affects neuronal function remains unclear. Tumor necrosis factor-α (TNFα) is a proinflammatory cytokine that regulates synapse function by controlling neurotransmitter receptor trafficking and homeostatic synaptic plasticity. Here we characterize the mechanisms through which TNFα regulates inhibitory synapse function in mature rat and mouse hippocampal neurons. Acute application of TNFα induces a rapid and persistent decrease of inhibitory synaptic strength and downregulation of cell-surface levels of GABA(A)Rs containing α1, α2, β2/3, and γ2 subunits. We show that trafficking of GABA(A)Rs in response to TNFα is mediated by neuronally expressed TNF receptor 1 and requires activation of p38 MAPK, phosphatidylinositol 3-kinase, protein phosphatase 1 (PP1), and dynamin GTPase. Furthermore, TNFα enhances the association of PP1 with GABA(A)R β3 subunits and dephosphorylates a site on β3 known to regulate phospho-dependent interactions with the endocytic machinery. Conversely, we find that calcineurin and PP2A are not essential components of the signaling pathway and that clustering of the scaffolding protein gephyrin is only reduced after the initial receptor endocytosis. Together, these findings demonstrate a distinct mechanism of regulated GABA(A)R endocytosis that may contribute to the disruption of circuit homeostasis under neuroinflammatory conditions.
authors.affiliation: Centre for Research in Neuroscience, Department of Neurology and Neurosurgery, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada H3G 1A4.
authors.forename: Horia
authors.initials: H
authors.lastname: Pribiag
authors.forename: David
authors.initials: D
authors.lastname: Stellwagen
mesh_terms: D000818:Animals; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D034281:Dynamins / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D011963:Receptors, GABA-A; D014409:Tumor Necrosis Factor-alpha; D054645:Protein Phosphatase 1; D034281:Dynamins